Is EVC p.Arg443Gln (c.1328G>A) pathogenic?

EVC p.Arg443Gln (c.1328G>A) is classified Benign/Likely benign in EVC (ClinVar, Multiple submitters, 15 submitters; last evaluated 2026-05-09). AlphaMissense: likely benign (0.069); Common (popmax 23%, afr) — too common for a highly-penetrant pathogenic allele; Associated with acrofacial dysostosis, Weyers type.

What condition is associated with EVC p.Arg443Gln (c.1328G>A)?

EVC p.Arg443Gln (c.1328G>A) is associated with acrofacial dysostosis, Weyers type, Ellis-van Creveld syndrome (ClinVar).

What do computational predictors say about EVC p.Arg443Gln (c.1328G>A)?

AlphaMissense predicts likely benign (score 0.069) — an in-silico prediction, not a clinical call.

EVC p.Arg443Gln

Q: How common is EVC p.Arg443Gln (c.1328G>A) in the general population?

EVC p.Arg443Gln (c.1328G>A) is common (popmax 23%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1328G>A · rs35953626 · VCV5342

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 15 submitters

AlphaMissense

likely benign

0.069 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 23%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

acrofacial dysostosis, Weyers type

Computational evidence

Protein change
AlphaMissense	0.069	likely benign
REVEL	0.058	moderately benign-leaning
SaProt	LLR -7.61	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.092	GERP -3, phastCons 0.01
Regional constraint	o/e 1.12	unconstrained · MANE · 100 kb · p 1.2e-05 · regional, not allelic
Overall
CADD	11.67	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 23% African / African-American · 17,265/74,988 alleles

Filtering AF 22.7% ClinGen BA1/BS1 input FAF95, joint · FAF99 22.6%

Overall 1.28% 20,670/1,614,078 alleles · common exomes 10,530/1,461,846 · genomes 10,140/152,232 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	23%	4
Admixed American	1.93%	52
Remaining individualsnot grpmax-eligible	1.85%	54
Middle Eastern	1.4%	71
European (non-Finnish)	0.0799%	1,251
South Asian	0.0582%	1,718
Ashkenazi Jewishnot grpmax-eligible	0.0372%	2,692
East Asian	0.00223%	44,860

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: EVC
Protein: p.Arg443Gln
Coding: c.1328G>A
MANE Select: NM_153717
dbSNP: rs35953626
Type: single nucleotide variant
Location: chr4:5753797 (GRCh38)
Gene constraint: LOEUF 1.134 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.49
Residue 443: a UniProt-annotated variant site (in evc)

Full EVC gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

acrofacial dysostosis, Weyers type — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Ellis-van Creveld syndrome

Similar variants

EVC p.Arg443Ter Pathogenic ★★ same residue
EVC p.Arg443= Likely benign ★ same residue
EVC c.1098+1G>A Pathogenic/Likely pathogenic ★★ same condition
EVC c.175-2A>G Pathogenic/Likely pathogenic ★★ same condition
EVC c.1777-1G>A Pathogenic/Likely pathogenic ★★ same condition
EVC c.1777-2A>G Pathogenic/Likely pathogenic ★★ same condition
EVC c.1886+1G>C Likely pathogenic ★★ same condition
EVC c.1886+5G>A Pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/evc-p-arg443gln (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown